In women with estrogen receptor-positive, hormone-refractory metastatic breast cancer, oral Z-endoxifen hydrochloride, the potent metabolite of tamoxifen, provided substantial drug exposure regardless of CYP2D6 genotype, acceptable toxicity, and promising antitumor activity, researchers reported.
Results from a phase I study in 38 patients with metastatic breast cancer demonstrated a clinical benefit rate (stable disease ≥ 6 months) of 26.3%. including a partial response by RECIST criteria in three patients who experienced progression during prior tamoxifen therapy, according to Matthew P. Goetz, MD, of the Mayo Clinic in Rochester, Minnesota, and colleagues.
Clinical benefit was also seen in seven patients who had no prior tamoxifen treatment or who didn’t experience progression with adjuvant tamoxifen. The median progression-free survival (PFS) time was 110 days, with a 1-year PFS rate of 15%, they wrote online in the Journal of Clinical Oncology.
The study was unable to determine the maximum-tolerated dose of oral endoxifen, and dose escalation was discontinued at 160 mg per day and endoxifen concentrations >1,900 ng/mL. At the time of data lock on March 5, 2017, seven patients had died due to metastatic breast cancer. Of the 31 patients who were alive, two did not have disease progression and 29 did.
Notably, CYP2D6 — the enzyme that converts tamoxifen to endoxifen — was not associated with either Z-endoxifen oral clearance or PFS, the study showed.
Based on these results, “The relationship between CYP2D6 genotype, endoxifen exposure, and the antitumor benefit of both drugs will be evaluated in the randomized phase II trial of Z-endoxifen and tamoxifen,” authors wrote. The trial will directly compare endoxifen (80 mg/day) with tamoxifen (20 mg/day) in women with prior aromatase inhibitor (AI) progression.
For the current study, 41 women were enrolled from March 25, 2011 to Dec. 9, 2014, and 38 were included in the maximum-tolerated dose (MTD) determination. A total of 36 patients experienced progression while on an AI, 21 while on fulvestrant (Faslodex), and 15 progressed on prior tamoxifen therapy.
Patients received 20, 40, 60, 80, 100, 120, or 160 mg of Z-endoxifen by mouth daily or until unable to continue treatment. Dose levels 40, 80, and 100 mg/day were also studied in the expansion phase of the trial. Of the 16 patients enrolled in the expansion cohorts, six were randomized to 40 mg/day, five to 80 mg/day, and five to 100 mg/day.
Dose-limiting toxicities were reported in two patients at the 60-mg dose: a pulmonary embolus after one cycle of treatment and a grade 4 hypertriglyceridemia after five treatment cycles. No eye toxicity was observed and there were no adverse effects reported in the expansion cohorts.
“Long-term studies will be necessary to fully evaluate the adverse effect profile of Z-endoxifen,” the authors said.
Other selective ER modulators (SERMs) have been shown to reduce cholesterol levels and endoxifen appears to do the same. Preliminary results suggest this new SERM reduces both total and LDL cholesterol levels.
Patients with low CYP2D6 enzyme activity exhibit significantly lower endoxifen concentrations when treated with tamoxifen, Goetz’s group pointed out. Data from this study indicate that even non-therapeutic levels of Z-endoxifen can have antitumor activity in patients experiencing progression with tamoxifen, they said.
Patients with prior tamoxifen exposure and a CYP2D6 activity score ≥2.0 generally had rapid clinical progression with a shorter median PFS compared with patients with reduced CYP2D6 metabolism and an activity score ≤1.5 (61 vs 132 days, respectively, P=0.046).
In an accompanying editorial, V. Craig Jordan, PhD, of the MD Anderson Cancer Center in Houston, said that while the value of endoxifen as a salvage therapy will be determined in future clinical studies, “this could just be the beginning of a new era. Perhaps it is the right time to consider improving women’s health with a new SERM.”
More than 30 years ago, Jordan — known as the “Father of Tamoxifen” — discovered that the drug’s anti-estrogenic properties could halt breast cancer growth, thus paving the way for SERMs.
Although AIs are the current standard of care in postmenopausal women with breast cancer, the consequences of long-term therapy remain a concern, he noted.
“Improvements in the use of SERMs may be an important first step in creating an improved quality of life for an aging population,” suggested Jordan, noting that using adjuvant tamoxifen therapy for 10 years makes it possible “to save the lives of 50% of patients with ER-positive breast cancer.”
In addition to potentially reducing risk of breast cancer recurrence, a new SERM might also improve overall health in menopausal women by lowering risk of osteoporosis, coronary heart disease, and stroke without increasing the odds of endometrial cancer, Jordan pointed out.
“It is not just about being alive; it is about being well,” he wrote.
The study was funded by the Mayo Clinic, the Regis Foundation, Prospect Creek Foundation, the George M. Eisenberg Foundation for Chanties, and the National Cancer Institute.
Goetz disclosed relevant relationships with Eli Lilly, bioTheranostics, RNA Diagnostics, Eli Lilly, and Pfizer. Co-authors disclosed multiple relevant relationships with industry.
Jordan disclosed no relevant relationships with industry.
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner